CSF from MS patients damage neurons in-vitro

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A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis

https://academic.oup.com/brain/advance- ... 01/5531715

Abstract

Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain.

To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions.

The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake.

Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of ‘virtual hypoglycosis’ induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.

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Comments on the previous paper. A new paper in “Brain” identifies molecular mechanisms causing neuronal damage in multiple sclerosis patients with progressive clinical deterioration:

https://asrc.gc.cuny.edu/headlines/2019 ... ogression/

Differences in the Cerebrospinal Fluid of MS Patients May Hold the Key to Therapies That Halt Progression

NEW YORK, July 15, 2019 — The disability burden for people with multiple sclerosis (MS) can vary significantly depending on whether they have a relapsing/remitting form of the disease, where they experience periods of clinical remission, or a progressive form, where they have continued neurological deterioration without clinical remission. Effective therapies exist for managing relapsing/remitting MS, but treatment for progressive MS has proved more challenging. Now, a new paper published in the journal Brain from researchers at the Advanced Science Research Center (ASRC) at The Graduate Center, CUNY and Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai has identified potential mechanisms that may inform the development of therapies that effectively manage progressive MS.

Previous research had suggested that dysfunction of neuronal mitochondria — the energy-producing subcellular organelles — occurs in the brains of MS patients with progressive clinical disability. However, the molecular mechanisms underlying this process remained elusive.

“Because the brain is bathed by the cerebrospinal fluid (CSF), we asked whether treating cultured neurons with the CSF from MS patients with a relapsing/remitting or a progressive disease course would possibly elicit different effects on neuronal mitochondrial function,” said the study’s primary investigator Patrizia Casaccia, Einstein Professor of Biology at The Graduate Center and founding director of the Neuroscience Initiative at the ASRC. “We detected dramatic differences in the shape of the neuronal mitochondria and their ability to produce energy. Only exposure to the CSF from progressive MS patients caused neuronal mitochondria to fuse and elongate while rendering them unable to produce energy. We therefore searched for potential mechanisms of CSF-induced neurodegeneration with the intent to define therapeutic strategies.”